Prevalence, trends, and factors associated with antipsychotic polypharmacy among medicaid-eligible schizophrenia patients, 1998–2000
Antipsychotic Polypharmacy Among Medicaid Patients
Prevalence, Trends, and Factors Associated With Antipsychotic Polypharmacy Among Medicaid-Eligible Schizophrenia Patients, 1998–2000 Rahul Ganguly, Ph.D.; Jeffrey A. Kotzan, Ph.D.; L. Stephen Miller, Ph.D.; Klugh Kennedy, Pharm.D.; and Bradley C. Martin, Ph.D. Received Aug. 15, 2003; accepted Feb. 17, 2004. From theDepartment of Pharmacy Administration, School of Pharmacy,University of Mississippi, Oxford (Dr. Ganguly); the DepartmentObjective: To determine the prevalence, trends, of Clinical and Administrative Pharmacy, College of Pharmacy (Drs.
and factors associated with antipsychotic polyphar-
Kotzan and Kennedy) and the Department of Psychology (Dr. Miller),
macy categorized according to type of antipsy-
University of Georgia, Athens; and the College of Pharmacy,
chotic and duration of use and to contrast usage
University of Arkansas for Medical Sciences, Little Rock (Dr. Martin).At the time this study was completed, Dr. Ganguly was enrolled as
patterns with published treatment guidelines. a Ph.D. candidate in the Pharmacy Care Administration GraduateMethod: A retrospective cohort study was de- Program at the University of Georgia, and Dr. Martin was affiliated
signed, and Medicaid recipients ≥ 16 years of age
with the Department of Clinical and Administrative Pharmacy,
with a schizophrenia diagnosis (ICD-9-CM =
College of Pharmacy, University of Georgia.
295.xx) between 1998 and 2000 were identified
Supported, in part, by grant award RO3HS10815-01 from the
from the California (20% random sample) and
Agency for Healthcare Research and Quality (AHRQ), Rockville, Md.Presented, in part, at the 8th annual international meeting of the
Georgia Medicaid claims databases. Use of anti-
International Society for Pharmacoeconomic Research, Arlington, Va.,
psychotic polypharmacy was categorized based on
duration (long-term polypharmacy was defined as
Corresponding author and reprints: Bradley C. Martin, Ph.D.,
lasting > 2 months), and long-term use was further
College of Pharmacy, University of Arkansas for Medical Sciences,
categorized based on type of antipsychotic combi-
4301 W. Markham St., Slot 522, Little Rock, AR 72205-7122(e-mail: [email protected]).
nations (clozapine, conventional, and atypical). The prevalence, mean duration, and frequency ofand yearwise trends in antipsychotic polypharmacywere estimated. A stepwise logistic variable selec-
t is estimated that antipsychotic polypharmacy, de-
tion procedure was used to identify factors associ-
Ifined as concomitant use of multiple antipsychotics,
ated with long-term antipsychotic polypharmacy.
is prescribed for up to 40% of schizophrenia patients.1
Results: Of a total of 31,435 persons with
schizophrenia, the 1998–2000 prevalence of anti-
However, there are no randomized controlled trials of
psychotic polypharmacy was 40% (N = 12,549;
combination therapy except for 1 with sulpiride and clo-
mean age = 43 years; white, 47%; female, 48%;
zapine, which provides little guidance in the United States
mean duration of polypharmacy = 149 days), and
since sulpiride is not available in the United States.2 Apart
long-term antipsychotic polypharmacy prevalence
from that study, there are case reports3–11 and open, uncon-
was 23% (N = 7222, mean duration = 236 days). The prevalence of atypical antipsychotic poly-
trolled, nonrandomized trials12–17 that report the effects
of antipsychotic polypharmacy. Many of these studies re-
(p < .0001). Use of newer atypicals such as quetia-
port improvements in symptom control3–5,7–9,11,12,15 and in-
pine (OR = 18.32) and older conventionals such as
stances of nonserious side effects such as drooling11 and
chlorpromazine (OR = 28.87) was strongly associ-
compulsive behavior.12 Other studies report an increased
ated with long-term antipsychotic polypharmacy. Conclusion: Antipsychotic polypharmacy
incidence of serious adverse events such as prolactin
is widely prevalent, is prescribed for long dura-
elevation, akathisia, and hypersalivation6,10,13,17 and even
tions, and is an increasing phenomenon among
an increased risk of mortality (study N = 88, relative
Medicaid-eligible schizophrenia patients, indicat-
risk = 2.46).16 However, it should be noted that besides
ing a significant discrepancy with treatment guide-
the obvious design limitations of such uncontrolled trials,
lines (which do not advocate the use of any poly-pharmacy except for short-term periods when
these studies were limited by small sample sizes (most of
transitioning patients to new antipsychotics).
them are 1- or 2-patient case reports), short follow-up pe-
Further research evaluating the effects of antipsy-
riods, and incomplete reporting of adverse effects. The re-
chotic polypharmacy in schizophrenia patients
cent introduction of 4 antipsychotics (olanzapine in 1996,
may assist in defining the scope and potential
quetiapine in 1997, ziprasidone in 2001, and aripiprazole
(J Clin Psychiatry 2004;65:1377–1388)
in 2003) with differing receptor profiles has further in-creased the possibilities of combining these agents. Theobjective of our study was to estimate the prevalence and
COPYRIGHT 2004 PHYSICIANS POSTGRADUA TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. Table 1. Antipsychotics Included in an Analysis Figure 1. Hypothetical Antipsychotic Polypharmacy Episode of Antipsychotic Polypharmacy Involving Risperidone and Haloperidol
ThioridazineThiothixeneTrifluoperazineChlorprothixene
trends of antipsychotic polypharmacy, categorize antipsy-
chotic polypharmacy according to type of antipsychoticand duration of use, and contrast antipsychotic polyphar-macy usage patterns with published treatment guidelines. We also estimated the factors associated with antipsy-
Medicaid reimburses 4 state psychiatric hospitals for in-
patient services rendered to Medicaid-eligible patients, sothere was no need to link state psychiatric hospitals with
The Georgia18–21 and California22–24 Medicaid data have
been used in the past for epidemiologic studies and have
A retrospective observational study design was em-
been found to be valid. The accuracy of schizophrenia di-
ployed using a combined 2-state Medicaid claims data-
agnoses in Medicaid claims data has also been validated
base. The study was approved by the University of Geor-
gia Institutional Review Board. Claims data from January1998 through December 2000 for Medicaid recipients
from the states of Georgia and California were combined
Persons with schizophrenia were identified using the
to build this 2-state database. Three sources of data were
following inclusion criteria: primary diagnosis of schizo-
used: the Georgia Medicaid files maintained by the Geor-
phrenia (ICD-9-CM = 295.xx) recorded on at least 1 paid
gia Department of Medical Assistance (GDMA), Georgia
claim during the period January 1998 through December
state-based institutional data files maintained by the De-
2000 and age of at least 16 years as of Jan. 1, 1998.
partment of Human Resources (DHR), and a CaliforniaMedicaid 20% random sample (Medi-Cal files).
The Medicaid files contain eligibility details, demo-
After the schizophrenia patients were identified, anti-
graphics, and claims history for various health care ser-
psychotic polypharmacy episodes for each person were
vices, including Medicaid paid amount, outpatient pre-
identified. For the purpose of this study, antipsychotic
scription drugs, inpatient stays, and disease diagnosis. A
polypharmacy was defined as 2 or more chemically dis-
common resource available to Georgia Medicaid patients
tinct antipsychotics prescribed concurrently with an over-
is the 8 psychiatric hospitals managed by the DHR that do
lap of at least 14 or more days of therapy.26 The list of
not bill Medicaid for services rendered to persons aged 21
antipsychotics is provided in Table 1. Antipsychotic poly-
to 64 years. Records from these 8 hospitals were com-
pharmacy episodes were constructed using a “date of ser-
bined to form the DHR file that contains a system-wide
vice” variable that recorded the prescription fill date and a
record of each visit a patient received at any of the 8
“days supply” variable that recorded the intended dura-
system inpatient institutions in operation. To capture
tion of each antipsychotic prescription filled for each per-
psychiatric episodes of care, we linked the DHR files
son. Figure 1 shows a hypothetical antipsychotic poly-
(state-based institutional data) by patient identifiers to
pharmacy episode involving risperidone and haloperidol.
the GDMA files (Georgia Medicaid claims data). These
The first day of the polypharmacy episode was considered
patient-linked or merged data provide a complete picture
of the medical resources consumed for each Medicaid-
An episode of antipsychotic polypharmacy was de-
eligible patient with schizophrenia in Georgia. California
fined as a period of continuous antipsychotic polyphar-
COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Antipsychotic Polypharmacy Among Medicaid Patients
Figure 2. Categories of Antipsychotic Polypharmacy and Monotherapy
macy without a break period of 31 or more days.27 A break
Identification of Factors Associated With
period was defined as a period when the patient had no
supply of drugs. Hospital stays that occurred within 31
To identify factors associated with long-term antipsy-
days of an antipsychotic use period were considered as
chotic polypharmacy, we included recipients who had
a continuation of the preceding episode and not a part
been treated with antipsychotic polypharmacy or mono-
of the break period if the therapy remained the same after
therapy for at least 61 days between 1998 and 2000. Anti-
psychotic use episodes in which a single antipsychotic
Antipsychotic polypharmacy was classified in a hierar-
was prescribed for at least 61 days without a break period
chical fashion, narrowing the definition of antipsychotic
of 31 or more days were referred to as monotherapy
polypharmacy with each consecutive step in accordance
with published treatment guidelines as displayed in Figure
Among these recipients, those who did not have at least
2. The Journal of Clinical Psychiatry treatment guideline28
6 months of continuous Medicaid eligibility prior to their
is the only guideline that offers guidance on the duration of
single longest polypharmacy or monotherapy episode
antipsychotic polypharmacy; it recommends polypharmacy
were excluded. In addition, recipients who did not have at
only when switching from one antipsychotic to another
least 1 paid claim every 90 days prior to their single long-
(cross-titration or overlap and taper) and for not more than
est polypharmacy or monotherapy episode were excluded.
8 weeks or 2 months. Other guidelines do not advocate
The latter criterion was applied to ensure that persons who
any antipsychotic polypharmacy. Based on the Journal of
were eligible for Medicaid benefits had not withdrawn
Clinical Psychiatry treatment guideline, a subject with an
from the system (e.g., were in prison).22 The single longest
episode of antipsychotic polypharmacy longer than 2
episode of antipsychotic polypharmacy or monotherapy,
months (at least 61 days) was categorized into the long-
i.e., period of maximum exposure to treatment, between
term antipsychotic polypharmacy cohort(s) (Figure 2).
1998 and 2000 was identified for each recipient. Depend-
Since clozapine is generally reserved for treatment-
ing on the type of antipsychotic polypharmacy or mono-
resistant and comparatively more ill patients, the long-term
therapy prescribed during the longest episode, e.g., long-
antipsychotic polypharmacy cohort was separated into clo-
term, clozapine, nonclozapine, clozapine + atypical, the
zapine and nonclozapine cohorts for analyses. The cloza-
recipient was grouped into one of the several long-term
pine and nonclozapine groups were further categorized into
polypharmacy or monotherapy groups (Figure 2).
clozapine subgroups (clozapine + atypical, clozapine +
A comprehensive list of possible factors associated
conventional) and nonclozapine subgroups (atypical +
with antipsychotic polypharmacy was identified by a sur-
atypical, atypical + conventional, conventional + conven-
vey of published literature and expert opinion (Table 2).
tional). The prevalence of each type of antipsychotic
This list included demographics, diagnosis-related co-
polypharmacy was calculated over the 3 years and sepa-
morbidities, drug classes, antipsychotic agents, and prior
rately for each year. The Cochran-Armitage trend test was
health care utilization variables. The diagnosis-related co-
performed to estimate temporal changes in prevalence of
morbidities and drug classes were obtained from a cost
antipsychotic polypharmacy, and t tests were performed to
prediction model for schizophrenia patients. This model
estimate differences in prevalence between various catego-
has been developed and validated on the Georgia Med-
icaid database as a part of an Agency for Healthcare Re-
COPYRIGHT 2004 PHYSICIANS POSTGRADUA TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. Table 2. Initial List of Candidate Factors Associated With Antipsychotic Polypharmacy Demographics
(antiarrhythmic + inotropic + vasopressor, ACE inhibitors,
(adrenergic bronchodilators + asthma vasopressors +
combinations, methylxanthines, inhalants + leukotrienes +
(hydantoin + succinimide + oxazolidinedione,
barbiturates + certain benzodiazepines, miscellaneous
anticonvulsants [valproic acid and derivatives, carbamazepine
and derivatives, gabapentin, lamotrigine, tiagabine, topiramate,
Hyperlipidemia, hypercholesterolemia drugs
Menopause drugs (hormone replacement therapy)
Pain (terminal) drugs, narcotic, analgesic
Rheumatoid arthritis/collagen vascular disease
Rheumatologic drugs/Crohn’s disease drugs/ulcerative colitis drugs
Atypicals: olanzapine, risperidone, quetiapine, clozapine
Conventionals: haloperidol oral and injectable, fluphenazine oral
and injectable, thioridazine, chlorpromazine, thiothixene
Depression or schizoaffective disorder†
Psychiatric inpatient episode, latest inpatient days,
Regular antipsychotic use (antipsychotic prescription filled every
aThe prior period was the 6 months preceding the polypharmacy or monotherapy episode. *Indicates that a hierarchy exists in relation to the cost categories below, which are denoted by a dagger (†). If both comorbidities were present,
only the higher cost category was counted.
Abbreviations: ACE = angiotensin-converting enzyme, AIDS = acquired immunodeficiency syndrome, ESRD = end-stage renal disease.
search and Quality project to develop risk adjustment
administration to differentiate between the injectable and
indices for persons suffering from schizophrenia. The
oral dosage forms; this was done because the injectable
month and year of the episode start date were also in-
forms are generally prescribed to a less compliant group
cluded to identify any yearwise or seasonal trend in use.
of patients28 and compliance in turn may be an important
The list of antipsychotic agents consisted of the 10 most
factor associated with choice of therapy.
prevalent drugs identified from a frequency analysis of
A stepwise logistic variable selection procedure was
the prescription records from the prior period (the 6
used to test the hypothesis that demographics, diagnosis-
months preceding polypharmacy or monotherapy). Halo-
related comorbidities, drug classes, antipsychotic agents,
peridol and fluphenazine were categorized by mode of
and prior health care utilization variables (identified in
COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Antipsychotic Polypharmacy Among Medicaid Patients
Table 3. Demographic Characteristics of a Sample Table 4. Prevalence of Long-Term Antipsychotic of Medicaid-Eligible Schizophrenia Patients at Least Polypharmacy in a Sample of Medicaid-Eligible 16 Years of Age Schizophrenia Patients at Least 16 Years of Age, 1998–2000
Table 2) are independently associated with long-term
antipsychotic polypharmacy. The binary treatment indi-
cator (1 = long-term antipsychotic polypharmacy, 0 =
monotherapy) was modeled, and main effects of the ini-
tial list of factors were entered into the model if they met
the significance level (p value) of .2 and removed if they
did not meet the significance level of .1. To guard against
model specification errors using stepwise procedures, we
developed the initial model with a 70% random sample
and utilized the remaining 30% of the subjects to validate
the final model. The primary analysis was performed to
identify factors associated with long-term antipsychotic
polypharmacy, since long-term usage is not a recom-
mended practice and is of greater policy relevance thanall usage that combines both short- and long-term use. Subanalyses were performed to identify factors associ-
(Table 4). California had a significantly higher prev-
ated with usage by type of antipsychotic, e.g., clozapine,
alence of antipsychotic polypharmacy across all the
atypical + atypical, atypical + conventional, and conven-
antipsychotic polypharmacy categories (p < .0001). The
tional + conventional polypharmacy, and any differences
prevalence of long-term polypharmacy was highest
from the primary analysis were reported. The database
among subjects exposed to clozapine (36.2%).
was managed using SAS software Version 8.02,29 and sta-
Among the 7222 persons with 1 or more long-term
tistical analysis was performed using SAS and STATA
episodes, there were over 2.0 episodes (95% CI = 2.0 to
2.1) per recipient between 1998 and 2000, with a meanduration of 236 days per episode (95% CI = 230.3 to
241.6) (Table 5). On average, a long-term polypharmacypatient was exposed to polypharmacy for a total of 1 year
(367 days) over the 3-year period, which after ad-
We found that 32,280 persons (Georgia, 18,373; Cali-
justment for differences in total months of Medicaid eli-
fornia, 13,907) had received at least 1 primary diagnosis
gibility translated to 388 days of polypharmacy for each
of schizophrenia between 1998 and 2000, of whom
recipient who was continuously eligible for 3 years. A
31,435 were at least 16 years of age as of Jan. 1, 1998,
trend was observed toward higher polypharmacy episode
and were retained in the cohort. The mean age of the
duration for California Medicaid recipients compared
31,435 persons was 43 years (SD = 14 years) (both Geor-
with Georgia recipients across all categories. Long-term
gia and California patients had mean ages of 43 years),
clozapine polypharmacy episodes had a longer mean du-
50% were female (Georgia, 56%; California, 43%), and
ration of 301 days than long-term nonclozapine poly-
46% were white (Georgia, 38%; California, 57%) (Table
pharmacy episodes, which lasted for a mean of 225 days
3). Of 31,435 persons, 88% (N = 27,757) had received at
least 1 prescription for an antipsychotic drug. Of those
Among the long-term antipsychotic polypharmacy
who received any polypharmacy, 48% were female and
groups, clozapine polypharmacy accounted for 11% of
47% were white. The overall prevalence of any antipsy-
all long-term polypharmacy, and atypical + conventional
chotic polypharmacy was 40% (N = 12,549) over the pe-
polypharmacy accounted for 68% of all long-term poly-
riod 1998–2000 and was 46% in California compared
with 35% in Georgia (p < .0001). The mean duration ofpolypharmacy was 149 days.
A total of 23% (N = 7222) of recipients had 1 or
The 3-year trend of long-term antipsychotic polyphar-
more long-term antipsychotic polypharmacy episodes
macy is presented in Figure 3. The overall prevalence
COPYRIGHT 2004 PHYSICIANS POSTGRADUA TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. Table 5. Number and Length of Long-Term Antipsychotic Polypharmacy Episodes by Type of Polypharmacy, 1998–2000
All long-term polypharmacyNo. of episodes
Long-term clozapine polypharmacyaNo. of episodes
Long-term nonclozapine polypharmacyNo. of episodes
aDefined as concurrent use of clozapine and a nonclozapine antipsychotic. At this level, “nonclozapine” is not differentiated into atypical or
conventional. Therefore, a clozapine + atypical episode and clozapine + conventional episode occurring within 31 days of each other would beconsidered 1 episode and not 2 separate episodes. Figure 3. Prevalence of Long-Term Antipsychotic Polypharmacy by Type, 1998–2000
of all antipsychotic polypharmacy increased significantly
ciated with antipsychotic polypharmacy. A total of 8757
from 32% in 1998 to 41% in 2000 (Cochran-Armitage
patients received long-term monotherapy and met the
test: p < .0001); the increase in Georgia was from 24% to
inclusion criteria. A 70% random sample, 4422 antipsy-
30% and in California from 43% to 62%. Except for cloza-
chotic polypharmacy subjects and 6162 monotherapy
pine + conventional polypharmacy (no change) and con-
subjects, was retained for the primary analysis, and the re-
ventional + conventional polypharmacy (decreased), all
maining subjects were analyzed separately to estimate the
antipsychotic polypharmacy prevalences increased from
validity of the final model specification. Table 6 provides
1998 through 2000 (Cochran-Armitage test: p < .0001).
the adjusted odds ratios, 95% confidence intervals, anddistribution of the factors identified from the stepwise lo-
Factors Associated With Antipsychotic Polypharmacy
gistic regression analysis for the long-term antipsychotic
Of the 7222 schizophrenia patients who received long-
polypharmacy outcome in the primary sample. Forty vari-
term antipsychotic polypharmacy between 1998 and 2000,
ables were retained in the final model, and all variables
6438 were continuously eligible for Medicaid and had at
were associated with long-term antipsychotic polyphar-
least 1 claim every 90 days in the 6-month period preced-
macy at a significance level of < .05 except for use of an-
ing the episode and were retained to study the factors asso-
tihypertensive drugs (p = .0579), insulins (p = .0649), and
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Antipsychotic Polypharmacy Among Medicaid Patients
Table 6. Independent Factors Associated With Long-Term Antipsychotic Polypharmacy Identified From the Stepwise Logistic Variable Selection Procedurea
Eligible for Medicaid in Georgia (vs California)
First- and second-line antihypertensive drugs
Exposure to 3 of 3 respiratory drug classesc
Exposure to 1 of 2 antiepileptic drug classesd
Hyperlipidemia, hypercholesterolemia drugs
Health care utilization in 6 months preceding therapy episode
Mental health cost in 6-month period, mean (SD), $
No. of psychiatric outpatient physician visits, mean (SD)
(antipsychotic prescription filled every 2 mo)
3rd quarter start date (July, August, September)e
4th quarter start date (October, November, December)e
aValues shown as N (%) unless otherwise noted. Association of predicted probabilities and observed responses: c-statistic for the final
model = 0.9143, c-statistic for validation sample = 0.9174.
bCardiac drug classes are (1) antiarrhythmic + inotropic + vasopressor, (2) angiotensin-converting enzyme (ACE) inhibitors, (3) antianginal agents,
cRespiratory drug classes are (1) adrenergic bronchodilators + asthma vasopressors + combinations, (2) methylxanthines,
and (3) inhalants + leukotrienes + combinations.
dAntiepileptic drug classes are barbiturates + certain benzodiazepines and miscellaneous anticonvulsants (valproic acid and derivatives,
carbamazepine and derivatives, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam).
fYear 1998 odds ratio = 1. Abbreviation: AIDS = acquired immunodeficiency syndrome. COPYRIGHT 2004 PHYSICIANS POSTGRADUA TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
gout drugs (p = .0906). The c-statistic for the model was
personality disorders (OR = 0.71) and drug use for car-
0.914 (0.5 for model with no predictive power; 1 for per-
diac conditions (OR = 0.81) were negatively associated
fect model), which shows that the model could discrim-
with long-term antipsychotic polypharmacy, although the
inate well between those who used long-term antipsy-
strength of association was low (p ~ .05) for AIDS and
chotic polypharmacy and those who used monotherapy.
The c-statistic for the final model in the 30% validation
No additional factors were identified in the clozapine
sample was 0.917, which shows that the model could dis-
polypharmacy versus clozapine monotherapy analysis.
criminate equally well between antipsychotic polyphar-
However, in the nonclozapine groups, arrhythmia (OR =
macy and monotherapy in an external sample and sug-
2.0, 95% CI = 0.97 to 4.33), chronic obstructive pulmo-
gests that the initial model was correctly specified.
nary disease (COPD) (OR = 1.7, 95% CI = 1.14 to 2.57),
Being eligible for Georgia Medicaid was significantly
asthma (OR = 2.3, 95% CI = 1.18 to 4.60), and compli-
associated with a reduced likelihood of receiving long-
cated diabetes (OR = 2.7, 95% CI = 1.10 to 6.90) were
term antipsychotic polypharmacy as compared with
positively associated with atypical + atypical polyphar-
being eligible for California Medicaid (OR = 0.62, 95%
macy; myocardial infarction (OR = 3.14, 95% CI = 0.90
CI = 0.54 to 0.70). Being of male gender and belonging
to 10.93) was associated with atypical + conventional
to the aid category (aged, blind, disabled) were associated
polypharmacy; and coagulopathy (OR = 6.8, 95% CI =
with an increased likelihood of receiving long-term anti-
1.14 to 40.94) was associated with conventional + con-
psychotic polypharmacy. Among the diagnosis-related
comorbidities, weight loss or malnutrition was stronglyassociated with long-term antipsychotic polypharmacy
(OR = 4.50, 95% CI = 1.54 to 13.17), although the abso-lute numbers were small in both the antipsychotic poly-
The Journal of Clinical Psychiatry treatment guide-
pharmacy and monotherapy groups. Diagnosis of epi-
line28 and some review articles on antipsychotic usage1,2,31
lepsy, other psychoses, and other mental disorders was
recognize antipsychotic polypharmacy as a possible
also positively associated with long-term antipsychotic
option in 2 specific situations: short-term or p.r.n. use
for “symptom control” and as a short-term tactic while
Among the drug classes, exposure to drugs used to
switching from one monotherapy to another. The Journal
treat Parkinson’s disease, respiratory disorders, and can-
of Clinical Psychiatry guideline is the only one that de-
cer was associated with long-term antipsychotic poly-
fines this short-term usage period, placing it at 2 months.
However, the authors also acknowledge the lack of pub-
All antipsychotic drugs selected in the model were
lished evidence and potential for adverse events with anti-
strongly associated (ORs of 5 to 28, p < .0001) with a
psychotic polypharmacy. Therefore, it is of concern to see
higher likelihood of long-term antipsychotic polyphar-
that 23% of patients received polypharmacy for more than
macy. Among the atypical antipsychotics, quetiapine
2 months and the mean duration of use was almost 8
had the highest positive association with long-term anti-
psychotic polypharmacy (OR = 18.32, 95% CI = 13.07
We found no previous studies that report prevalence
to 25.68), followed by olanzapine (OR = 14.45) and ris-
data for Medicaid-eligible schizophrenia patients or any
peridone (OR = 9.18). Among the conventionals, chlor-
that report prevalence of long-term polypharmacy for any
promazine (OR = 28.87, 95% CI = 21.14 to 39.42),
population. However, the overall combined prevalence
followed by thioridazine (OR = 18.61) and thiothixene
rate of long-term and short-term polypharmacy in our
(OR = 8.44), had the highest positive associations. Cloza-
study was similar to that reported in a 1985 survey of 768
pine (OR = 11.77) was also associated with long-term
patients in 8 countries (overall prevalence = 40%, U.S.
prevalence = 36%)1 but was considerably higher than the
Among the prior utilization variables, regular antipsy-
prevalence reported in a more recent Veterans Affairs
chotic use (1 antipsychotic prescription filled every 2
(VA) study looking at data over a short 4-month time pe-
months) was associated (OR = 4.8) with long-term anti-
riod (6.8%)32 and was also higher than those in a 1-year
psychotic polypharmacy. Among the temporal variables,
prevalence study using physician office–based data from
index dates in the fourth quarter (October, November,
1997 (16.7%)33 and a Canadian study of hospital out-
December) had a higher association with antipsychotic
patients (27.5%).34 Some of the factors responsible for a
polypharmacy (OR = 2) compared with those in the first
higher prevalence estimate in our study could be a longer
quarter. Also, the years 1999 (OR = 5.53) and 2000
study time frame (the VA study captured prescription
(OR = 9.67) had a higher association with long-term anti-
records during a 1-week period), a more recent year of
psychotic polypharmacy compared with 1998.
study (the physician office–based study was performed in
Diagnosis of acquired immunodeficiency syndrome
1997), Medicaid system-specific policies (California and
(AIDS) (OR = 0.52), alcohol abuse (OR = 0.58), and
Georgia Medicaid had removed a prior authorization rule
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Antipsychotic Polypharmacy Among Medicaid Patients
restricting newer antipsychotic use in 1997, which may
lence of long-term antipsychotic polypharmacy was 36%
have increased antipsychotic switches, inflating our prev-
in the clozapine-exposed group, which was higher than in
alence estimates), and analysis of a Medicaid population,
the atypical (29%) and conventional groups (31%), sug-
which is considered a more ill group of patients than non–
gesting refractory patients and less control with mono-
Medicaid-eligible persons with schizophrenia.
The 11% difference in prevalence of long-term poly-
The long-term nonclozapine atypical + conventional
pharmacy between California and Georgia is interesting.
group had the highest prevalence, 16%. The therapeutic
Additionally, the rate of increase in the prevalence of
actions of conventional antipsychotic drugs are due to
long-term antipsychotic polypharmacy from 1998 to
blockade of dopamine (D ) receptors, whereas the atypi-
2000 was notably higher in California (19%) than in
cal antipsychotics block both D and serotonin 5-HT
Georgia (6%). There are several potential reasons for this
receptors.35 Due to the differing receptor profiles, there
occurrence. First, these findings could be a result of dif-
may be a pharmacologic justification for combining
ferences in reimbursement policies. We compared the
atypicals with conventionals and using them for a long
prescription and inpatient reimbursement policies be-
duration, but there are no clinical studies that provide evi-
tween the 2 states and found no substantial difference.
dence for such use. Individuals in the atypical + conven-
Both states had rules requiring prior authorization for
tional group in our study could have been patients receiv-
atypical agents before 1998, reimbursed mental health
ing treatment on a switchover or p.r.n. basis who were
hospitalizations, had state psychiatric hospitals that bill
started on a short-term combination therapy and then re-
Medicaid, and had similar treatment authorization proce-
mained on it for some reason. For example, the therapy
dures. However, we cannot discount the fact that there
may have been continued if a patient was stable and the
could have been policy changes between 1998 and 2000
physician did not want to risk a relapse; this has been
that we are not aware of that could have driven these
quoted as a reason in a study of antipsychotic polyphar-
prevalence rates. Second, the difference in prevalence
macy.36 Physicians may also be observing that their pa-
rate could be a reflection of dissimilar prescribing habits
tients are stabilized on atypical + conventional combina-
in the 2 states. However, among schizophrenia patients
tion treatment and that there is real merit to such therapy.
who received at least 1 prescription for an antipsychotic,
It is possible that diagnosis of epilepsy and drug use
antipsychotic prescribing rates, which are a marker for
for Parkinson’s disease may be predictors of long-term
prescribing habits, were similar in the 2 states (atypicals:
antipsychotic polypharmacy, as presence of these com-
Georgia, 49%; California, 48%; conventionals: Georgia,
mon conditions may induce a physician to switch to a
47%; California, 44%) except for clozapine (Georgia,
better-tolerated treatment. However, since our study did
4%; California, 7%). Other process-related measures, for
not have a medication-free washout period (49% of the
example, the average number of physicians seen by Cali-
antipsychotic polypharmacy patients had received poly-
fornia subjects compared with Georgia subjects, could be
pharmacy in some prior period), these could be side ef-
responsible for the difference in long-term polypharmacy
fects of prior treatment with antipsychotic polypharmacy
rates. These are, however, speculations and cannot be
or monotherapy. The association between diagnosis of
cardiac arrhythmia and nonclozapine atypical + atypical
The rising trend for all atypical polypharmacy com-
polypharmacy (OR = 2.0) was as expected, given that
binations (atypical + atypical, atypical + conventional,
cardiovascular side effects such as tachycardia are com-
atypical + clozapine) may be because of increased avail-
mon with atypical monotherapy. Although a causal rela-
ability of newer antipsychotics or changing prescribing
tionship cannot be established from our analysis, this as-
habits. As newer antipsychotics become available, there
sociation may reflect an increased risk of cardiac side
is a higher probability of receiving antipsychotic poly-
effects with atypical polypharmacy. At the same time,
pharmacy as patients on treatment with older antipsy-
this association may be indicative of an effort to reduce
chotics are switched to newer medications. The rise in
cardiovascular side effects by titrating the patient to a
atypical polypharmacy could also be due to changing pre-
better-tolerated therapy. However, in the absence of any
scribing habits among physicians as they find success and
other information on this association, it might be prudent
a growing confidence in treating patients with antipsy-
to exercise caution, e.g., regular electrocardiogram moni-
toring, especially while adding one atypical to another.
Long-term clozapine polypharmacy episodes had a
Similarly, Parkinson’s disease was strongly associated
mean duration of 301 days (95% CI = 281 to 320) and
(p < .0001) with nonclozapine polypharmacy involving
lasted longer than nonclozapine episodes (225 days, 95%
conventional antipsychotics (OR > 3.5). The positive as-
CI = 219 to 231); this may be explained by the fact that
sociation between complicated diabetes and atypical +
clozapine is reserved for treatment-refractory patients
atypical polypharmacy may reflect recent concerns about
who require longer durations of treatment than the rela-
the occurrence of diabetes associated with the use of
tively better controlled nonclozapine patients. The preva-
olanzapine.37 The positive association between asthma/
COPYRIGHT 2004 PHYSICIANS POSTGRADUA TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
COPD and atypical + atypical polypharmacy may be ex-
pharmacy. The annual cost to the Medicaid systems of
plained through evidence in the medical literature that
adding a second antipsychotic in 2000 U.S. dollars was
suggests noncausal mechanisms such as noncompliance to
$494,877 for Georgia and $6,032,775 for California. From
asthma therapy in this population and causal mechanisms
a policy perspective, if Medicaid considered implement-
such as depression of the central nervous system and im-
ing a prior authorization rule for long-term polypharmacy
paired respiratory drive during asthma attacks.38
(usage beyond 60 days), the Medicaid systems could save
The odds ratios for all of the antipsychotic drugs
$412,397 and $5,027,312 per year in antipsychotic pre-
were high because we included only antipsychotics that
scription costs in Georgia and California, respectively.
were highly prevalent in the long-term polypharmacy co-
These estimates are based only on the incremental cost of
hort. We did this because we were interested in under-
the additional antipsychotic drugs when used concurrently
standing the relative effects of being prescribed these 10
with another antipsychotic and do not include any admin-
drugs, which are evident from the odds ratios. One of the
istrative or indirect costs (savings) such as drug level
interesting findings was that being placed on more re-
monitoring costs or additional or reduced hospitalizations
cently marketed atypical antipsychotics was associated
that may be associated with polypharmacy.
with an increased likelihood of being exposed to long-
The higher cost in California was driven by the fact that
term polypharmacy; for example, for quetiapine, launched
California has a larger Medicaid population, higher preva-
in 1997, OR = 18.32; for olanzapine, launched in 1996,
lence of clozapine + atypical and atypical + atypical poly-
OR = 14.45; and for risperidone, launched in 1994, OR =
pharmacy, and longer durations of polypharmacy. It is also
9.18. One explanation for this could be that more people
important to note that in California there was a 9-fold
on treatment with the most recent atypical compared with
increase in the likelihood of atypical + atypical long-term
other medications are in a switchover stage. This trend
polypharmacy in 1999 over 1998 and that there was a
was similar across all the groups. Also, use of low-potency
21-fold increase in 2000. This change was the highest
antipsychotic medications such as quetiapine or chlorpro-
among all other antipsychotic polypharmacy groups.
mazine was strongly associated with long-term antipsy-
While evaluating these speculative cost estimates, it is im-
portant to bear in mind that they are based on average
Long-term antipsychotic polypharmacy also raises
wholesale prices and recommended daily dosing, which
some financial concerns, as the Medicaid systems have
act as proxy measures for Medicaid-specific drug prices
limited resources that are being allocated to expensive
and actual average prescribed doses, respectively.
antipsychotic therapy. The clozapine + atypical and atypi-
Some of the limitations of the study are that inpatient
cal + atypical combinations are especially expensive, and
medication use is not recorded in this database and has not
the atypical + atypical combinations have been mentioned
been accounted for except where the patient was pre-
as cost drivers and a concern in the California Medicaid
scribed the same medication before and after hospitaliza-
system.39 Using the estimates for mean length of episode,
tion. In that case, the patient was assumed to be on that
number of episodes, prevalence by type of polypharmacy
medication during the inpatient stay. As mentioned earlier,
and a per-day average cost of antipsychotic,40 we calcu-
we singled out the longest episodes in our analysis to iden-
lated a rough speculative estimate* for the excess antipsy-
tify factors associated with polypharmacy. The identified
chotic cost per year to Medicaid due to long-term poly-
longest episode may not be the first episode of antipsy-chotic polypharmacy (49% of the polypharmacy patientshad received polypharmacy in the prior period) for the pa-
*Drug cost per day was calculated as the unit cost (average wholesale
tient in the study period. Therefore, treatment factors, for
price) of each drug multiplied by the average maintenance phase daily
example, comorbid conditions or medication use, cannot
dose (mg/day) of the drug as derived from the Journal of Clinical Psy-
be interpreted as predictors of antipsychotic polyphar-
chiatry treatment guideline. The average maintenance phase dailydoses for commonly prescribed agents were olanzapine 10 mg, risperi-
macy as they may be the result of prior polypharmacy
done 4 mg, quetiapine 300 mg, haloperidol 5 mg, fluphenazine 5 mg,
and thioridazine 300 mg. A weighted average daily cost of atypicals
Unless specifically mentioned, prevalence data re-
(~ $8) and conventionals (~ $0.23) was obtained using the product-specific drug cost per day and the utilization of the different atypical
ported here have not been adjusted for the fact that total
and conventional drugs observed in Georgia and California Medicaid.
months of Medicaid eligibility over the 3-year period var-
The annual cost of adding a second antipsychotic was calculated sepa-
ied between recipients. However, this may have affected
rately for each polypharmacy group by multiplying the weighted aver-age daily cost for atypical or conventional, multiplied by the average
the results marginally, because over 90% of polypharmacy
duration of polypharmacy, multiplied by the number of episodes of that
subjects were continuously eligible for more than 2
polypharmacy combination. It was assumed that when there were com-
years and 79% were continuously eligible for all 3 years.
binations using conventional drugs, the conventional drug would be thedrug discontinued and represent the incremental cost (atypicals and clo-
Additionally, the eligibility profile was very similar
zapine were assumed to be the drugs that would be kept if the patient
(California vs. Georgia, 78% vs. 80% continuously eli-
had to be treated with only 1 antipsychotic), and atypical costs were
gible for 3 years) for both states and would not have
counted only for atypical + atypical or clozapine + atypical polyphar-macy episodes. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
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Written by Professor Hywel Williams, Dr Ruth Murphy, Dr Jane Ravenscroft, Nurse Consultant Sandra Lawton and parentson behalf of the Nottingham Support Group for Carers of Children with Eczema. Scalp Ringworm (tinea capitis) - Information for Parents Introduction Ringworm is not a worm. It is a general term for a common fungus infection of the skin. It is called ringworm becausethe inf
IMPORTANT: PLEASE READ PART III: CONSUMER INFORMATION ending in “caine”, or to chlorhexidine or chlorhexidine- Instillagel® containing medicines or chlorhexidine-coated catheters • there is an infection, cut or rash at or near the area where This leaflet is part III of a three-part "Prescribing Information" published when Instillagel® was approved for sale in Canada